Project Summary/Abstract Preterm birth (PTB) is a leading cause of infant mortality and morbidity in the US and the globe, and can lead to a cascade of health problems later in life. Despite decades of research, our ability to predict and prevent PTB remains poor. Maternal stress preconception and during pregnancy is emerging as an important modifiable risk factor of PTB, but previous studies have yielded inconsistent findings. While methodological variations in study designs and stress measurements across studies may have contributed to these inconsistencies, another possibility, the individual difference in susceptibility to stress, has received increasing attention but has not yet been well studied. Research by others and us suggests that several factors are at play: gene environment interactions may play an important role in PTB, maternal stress may lead to epigenetic changes, and maternal epigenetic alterations are associated with PTB; yet these data remain fragmented. This proposed study offers an exceptional opportunity to investigate these factors and fill in the aforementioned gaps to connect the dots. We propose to utilize the existing databases of the Boston Birth Cohort, including maternal stress data, genome-wide genotype data, epigenome-wide DNA methylation data as well as extensive covariables from 2,000 African American mothers (~800 PTBs). We aim to address the following novel aims: Aim 1. To study the interactions of maternal stress and maternal genome on PTB risk. We hypothesize that high levels of maternal stress (including self-reported psychosocial stress and physician-diagnosed emotional disorders preconception and during pregnancy) are associated with an increased risk of PTB, and that the associations between maternal stress and PTB are modified by maternal genotypes. Aim 2. To study the role of maternal epigenome in mediating maternal gene stress interactions on PTB risk. We hypothesize that maternal DNA methylation (DNAm) can mediate the associations between maternal stress and PTB risk; as well as the associations between maternal gene stress interactions and PTB risk, as identified in Aim 1. To address these aims, we will employ both a hypothesis-driven and a genome-wide approach, and will replicate our findings in independent multi-ethnic samples. While PTB will be the primary outcome, we will also explore PTB subtypes and related traits as the secondary outcomes. This proposed study would be the first to explore the complex interplay of maternal stress, genome, and epigenome on PTB in a high-risk US minority population. It will lay the groundwork to better understand the role of stress in PTB, especially individual susceptibility to stress and underlying epigenetic mechanisms. Findings from this study will be directly relevant to high risk urban, low income, African American populations, and may help to inform novel interventions to reduce the persistent and striking Black- White PTB disparity.